Adefovir

[Adefovir Dipivoxil-induced Fanconi's Syndrome and Osteomalacia Following Multiple Bone Fractures in a Patient with Chronic Hepatitis B].[Pubmed:30930400]

Yakugaku Zasshi. 2019;139(4):641-645.

We herein present the case of a 66-year-old Japanese man with Fanconi's syndrome. He had been receiving Adefovir dipivoxil (ADV) for the treatment of entecavir (ETV)-resistant chronic hepatitis B (CHB) for four years in his 8-year treatment of hepatocellular carcinoma (HCC), but was referred to our hospital after increased levels of bone pain in his ribs, knees, and ankles. Renal dysfunction, hypophosphatemia, and increased levels of bone alkaline phosphatase were found by a hematology test after admission for treatment of HCC. Radiography and 99m Tc-labeled hydroxymethylene diphosphonate (HMDP) scintigraphy revealed multiple insufficiency fractures in the ribs, knees, ankles, and heels. After switching from ADV to tenofovir disoproxil fumarate (TDF) and treatment with calcitriol and sodium dihydrogenphosphate, the patient's serum phosphate levels slightly increased and renal dysfunction did not improve, but after six months his clinical symptoms disappeared. To detect and prevent adverse effects from ADV, physicians and pharmacists should carefully monitor renal function and serum phosphate levels in patients with hepatitis B virus (HBV) treated for a long time with ADV.

Adefovir accumulation and nephrotoxicity in renal interstitium: Role of organic anion transporters of kidney.[Pubmed:30902543]

Life Sci. 2019 Mar 19. pii: S0024-3205(19)30206-1.

Common characteristics of drug induced nephrotoxicity are renal tubular and interstitial injury. Many studies have only focused on renal tubular injury. However, less is known about the effects of drugs in the renal interstitium on the nephrotoxicity. The aim of this study was to investigate the pharmacokinetics of Adefovir (ADV) and the nephrotoxicity in the renal interstitium. Rats were treated with ADV alone or in combination with probenecid for 1, 7, 14, or 28days. The renal interstitial fluid was collected by renal microdialysis. The concentration of ADV was determined by HPLC-MS/MS. Nephrotoxicity was evaluated by biochemical parameters or histological analysis. The results showed that organic anion transporters (OATs) inhibitor probenecid significantly increased the area under concentration-time curves (AUC) and peak concentration (Cmax) of ADV in the renal interstitium, while the clearance (CL) in the renal interstitium was decreased in the ADV plus probenecid group compared to the ADV groups. After long-term treatment, interstitial fibrosis was present in the ADV plus probenecid group, whereas no trace of that could be detected in the ADV groups. Furthermore, a decrease was observed in the expression of OATs/Oats, which was dependent upon the concentrations and time of ADV treatment. In conclusion, it is possible that ADV could be accumulated in the interstitium when Oats were inhibited, which could cause renal interstitial fibrosis. Simply reducing cell uptake in long-term treatment might not be an effective method to protect against chronic nephrotoxicity.

Comparison of the 48-week efficacy of Lamivudine plus Adefovir or Entecavir monotherapy in patients with HBeAg negative hepatitis following Lamivudine treatment failure.[Pubmed:30888751]

Acta Gastroenterol Belg. 2019 Jan-Mar;82(1):31-34.

AIMS: To compare the efficacy of treatment with lamivudine (LAM) plus Adefovir (ADV) or entecavir (ETV) monotherapy in LAM treatment failure patients with HBeAg negative chronic hepatitis B (CHB) patients during 48 weeks of therapy. PATIENTS AND METHODS: Thirty patients with HBeAg negative CHB were enrolled in the study. The serum levels of HBV DNA, HBsAg/HBsAb, and ALT were assessed by enzyme-linked immunosorbent assay at 0, 12, 24, 36, and 48 weeks. RESULTS: The rate of undetectable HBV DNA in the LAM+ADV group was 100%, which was higher than the ETV group at 48 weeks (73.33%, chi2 = 4.615, P = 0.032). Multivariate analysis using the Cox proportional hazards model showed that therapy with LAM+ADV or baseline levels of HBV DNA <107 copies/ml were independent predictive factors for undetectable HBV DNA rates in all patients (RR: 2.488, P = 0.042; RR: 0.201, P = 0.035). CONCLUSIONS: During the 48 weeks of treatment in patients with HBeAg negative CHB, LAM plus ADV suppressed HBV replication more effectively than ETV monotherapy. In addition, no virologic breakthrough was detected in the LAM add-on ADV group. Additionally, therapy with LAM+ADV or baseline levels of HBV DNA <107copies/ml were independent predictive factors for undetectable HBV DNA rates in patients.

Monotherapy with Tenofovir Disoproxil Fumarate for Adefovir-Resistant vs. Entecavir-Resistant Chronic Hepatitis B: a 5-Year clinical trial.[Pubmed:30876946]

J Hepatol. 2019 Mar 12. pii: S0168-8278(19)30142-4.

BACKGROUND AND AIMS: Tenofovir disoproxil fumarate (TDF) monotherapy has displayed non-inferior efficacy compared with TDF plus entecavir (ETV) combination therapy in patients with hepatitis B virus (HBV) resistant to ETV and/or Adefovir (ADV). Nonetheless, the virologic response rate was suboptimal up to 144 weeks of TDF monotherapy with uncertain long-term safety. METHODS: One trial enrolled patients with ETV resistance without ADV resistance (n=90), and another trial included patients with ADV resistance (n=102). Most patients (91.2%) also had LAM resistance. Patients were randomized 1:1 to receive TDF monotherapy or TDF+ETV combination therapy for 48 weeks, and then TDF monotherapy until 240 weeks. We compared efficacy between the studies and safety in the pooled population at 240 weeks. RESULTS: At week 240, the proportion of patients with serum HBV DNA <15 IU/mL was not significantly different between the ETV and ADV resistance groups in the full analysis set (84.4% vs. 73.5%; P=0.07), which was significantly different by on-treatment analysis (92.7% vs. 79.8%; P=0.02). Virologic blips associated with poor medication adherence occurred in 7 patients throughout the 240 weeks. None developed additional HBV resistance mutations. Among the 170 HBeAg-positive patients at baseline, 12 (7.1%) achieved HBeAg seroconversion at week 240. None achieved HBsAg seroclearance. Significant decreases from baseline were observed at week 240 in the estimated glomerular filtration rate (-3.21 mL/min/1.73 m(2) by the CKD-EPI equation, P<0.001) and bone mineral density (g/cm(2)) at the femur (-2.48%, P<0.001). CONCLUSIONS: TDF monotherapy provided an increasing virologic response rate for up to 240 weeks in heavily pretreated patients with HBV resistant to ETV and/or ADV. However, it was associated with poor serological responses and decreasing renal function and bone mineral density. LAY SUMMARY: In patients chronically infected with hepatitis B virus resistant to multiple drugs including lamivudine, entecavir, and/or Adefovir, tenofovir disoproxil fumarate (TDF) monotherapy showed non-inferior efficacy compared with the combination therapy with TDF plus entecavir. Nonetheless, short-term TDF monotherapy was associated with suboptimal virologic response, and its long-term safety was uncertain. This study displayed that 240 weeks of TDF monotherapy provided a virologic response in most of those patients, but was associated with poor serological responses and decreasing renal function and bone mineral density.

Adefovir dipivoxil sensitizes colon cancer cells to vemurafenib by disrupting the KCTD12-CDK1 interaction.[Pubmed:30872078]

Cancer Lett. 2019 Jun 1;451:79-91.

Vemurafenib is a B-Raf V600E inhibitor that exerts significant inhibitory effects in melanoma but not in colon cancer, and the mechanism of vemurafenib resistance remains unclear. In this study, bioinformatics analysis of gene profiles in cancer cells treated with vemurafenib or its analog revealed that cell cycle progression is significantly affected by vemurafenib. We found that CDK1 is stably activated in the vemurafenib-resistant (VR) colon cancer sublines that we established, indicating that CDK1 activation is responsible for vemurafenib resistance. As the KCTD12-CDK1 interaction is necessary for CDK1 activation, we screened an FDA-approved drug library consisting of 616 compounds and identified that Adefovir dipivoxil (AD), a nucleoside analog for treatment of HBV infections, disrupts the CDK1-KCTD12 interaction and induces G2 phase arrest in the cell cycle. Functional assays demonstrated that AD significantly inhibited colon cancer cell proliferation and tumorigenesis both in vitro and in vivo with no observed side effects. Furthermore, AD sensitized vemurafenib-resistant colon cancer cells and tumor xenografts to vemurafenib. This study reveals that CDK1 activation induces vemurafenib resistance and that AD is a promising therapeutic strategy for colon cancer both as a single agent and in combination with vemurafenib.

Adefovir (GS-0393) is an adenosine monophosphate analog antiviral agent that after intracellular conversion to Adefovir diphosphate inhibits HBV DNA polymerase. Adefovir has an IC50 of 0.7 μM against HBV in the HepG2.2.15 cell line. Adefovir has good antiviral activity against several viruses, including HBV and herpesviruses.

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